Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG) C-M Wendtner 1,6 , M Ritgen 2 , CD Schweighofer 1,6 , G Fingerle-Rowson 1,6 , H Campe 3 , G Ja ¨ger 3 , B Eichhorst 1 , R Busch 4 , H Diem 5 , A Engert 6 , S Stilgenbauer 7 , H Do ¨ hner 7 , M Kneba 2 , B Emmerich 8 , M Hallek 1,6 and the German CLL Study Group (GCLLSG) 1 Klinikum Grosshadern, Medical Clinic III, Ludwig-Maximilians-University, Munich, Germany; 2 Medical Clinic II, University Hospital, Kiel, Germany; 3 Max-von-Pettenkofer-Institute, Ludwig-Maximilians-University, Munich, Germany; 4 Institute of Medical Statistics and Epidemiology, Technical University, Munich, Germany; 5 Clinical Chemistry, Ludwig-Maximilians- University, Munich, Germany; 6 Medical Clinic I, University Hospital, Cologne, Germany; 7 Medical Clinic III, University Hospital Ulm, Germany; and 8 Medizinische Klinik Innenstadt, Ludwig-Maximilians-University, Munich, Germany Patients with CLL responding to initial chemotherapy with fludarabine alone (F) or in combination with cyclophosphamide (FC) were randomized for treatment with alemtuzumab (30 mg i.v. TIW, 12 weeks) or observation. Of 21 evaluable patients, 11 were randomized to alemtuzumab before the study was stopped due to severe infections in seven of 11 patients. These infections (one life-threatening pulmonary aspergillosis IV; four CMV reactivations III requiring i.v. ganciclovir; one pulmonary tuberculosis III; one herpes zoster III) were successfully treated and not associated with cumulative dose of alemtuzumab. In the observation arm, one herpes zoster infection II and one sinusitis I were documented. At 6 months after randomization, two patients in the alemtuzumab arm converted to CR, while three patients in the observation arm progressed. After alemtuzumab treatment, five of six patients achieved a molecular remission in peripheral blood while all patients in the observation arm remained MRD-positive (P ¼ 0.048). At 21.4 months median follow-up, patients receiving alemtuzumab showed a significant longer progression-free survival (no progression vs mean 24.7 months; P ¼ 0.036). In conclusion, a consolidation therapy with alemtuzumab is able to achieve molecular remissions and longer survival in CLL, but a safe treatment regimen needs to be determined. Leukemia (2004) 18, 1093–1101. doi:10.1038/sj.leu.2403354 Published online 8 April 2004 Keywords: CLL; alemtuzumab; consolidation; survival; MRD; CMV Introduction Fludarabine induces higher remission rates and longer progres- sion-free survival in comparison to alkylating agents in untreated patients with CLL. 1,2 Nevertheless, the majority of patients in remission relapse after a median of 20–30 months. One strategy to prolong progression-free survival (PFS) in these patients is to combine fludarabine with alkylating agents. 3,4 Another option currently under investigation is high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell support, 5 or more recently to combine established chemotherapy regimens with immunotherapy. The anti-CD20 antibody rituximab was shown to be very effective against CLL in combination with fludarabine-based chemotherapy with high rates of complete remissions. 6 The monoclonal antibody alemtuzumab, a huma- nized anti-CD52 antibody, has shown activity alone and in combination for patients with refractory CLL with an overall response rate of 33%, and was also proven effective in initial treatment of CLL patients, with approximately 80% of patients achieving durable responses. 7–12 Encouraging results have been published for the in vivo purging of residual disease after alemtuzumab consolidation. 13 Alemtuzumab lyses normal and malignant lymphocytes by antibody-dependent cellular cyto- toxicity (ADCC), complement activation and direct induction of apoptosis. 14–17 Besides effects against malignant lymphocytes in blood, alemtuzumab shows activity against lymphocytes de- rived from bone marrow and spleen, but is less active against nodal or extranodal masses. 9 Since CD52 is not expressed on CD34 þ hematopoietic stem cells, therapy with alemtuzumab does not preclude stem cell collection and further high-dose concepts. 18 Therefore, the aim of this study was to assess the safety profile, feasibility and efficacy of alemtuzumab as a consolidation therapy to improve the quality of remission and to eradicate minimal residual disease in patients responding to a first-line fludarabine-based chemotherapy. Patients and methods Study design The German CLL Study Group (GCLLSG) conducted an open- label, randomized phase III trial (CLL4B protocol) at 13 academic centers throughout Germany and Austria. The objective of the study was to assess the efficacy of alemtuzumab as consolidation therapy for patients with advanced B-CLL, who have responded to a first line chemotherapy with fludarabine (F) or fludarabine/cyclophosphamide (FC) (Eichhorst et al, Blood 2003; 102: 72, abstract). Patients were stratified according to induction treatment and response to induction treatment and randomized for treatment with alemtuzumab or observation. The primary end point was PFS defined as the time between start of F or FC until progression of disease or death. Secondary end points were clinical responses as assessed according to NCI-WG criteria, 19 molecular response rates, overall survival, drug safety and in particular the occurrence of severe infections. Toxicity was graded according to the common toxicity criteria (CTC). 20 The study was approved by the local ethics committee, and all patients gave written, informed consent prior to enrollment. Received 13 November 2003; accepted 1 March 2004; Published online 8 April 2004 Correspondence: Prof Dr Michael Hallek, Klinik I fu ¨ r Innere Medizin, Klinikum der Universita ¨t zu Ko ¨ln, Joseph-Stelzmann-Strasse 9, D-50924 Ko ¨ ln, Germany; Fax: þ 49 221 478 5455 Presented, in part, at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31–June 3, 2003, and the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6–9, 2003. Supported by a research grant of Schering AG, Berlin and MedacSchering Onkologie, Germany. V H sequencing was supported by a research grant from the Else Kro ¨ ner-Fresenius Stiftung, Germany. 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